Lower CR Rate Research Articles

Dose Dense/Dose Intense ABVD without Radiotherapy: A New Early Intensification Treatment Approach in Advanced-Stage Hodgkin Lymphoma. Ten Years Experience and Analysis of a Consecutive Series of 172 Previously Untreated Classic Hodgkin’s Lymphoma Patients

Despite impressive cure rates obtained with modern chemotherapy, the optimal therapeutic strategy in advanced classic Hodgkin Lymphoma (HL) is still debated due to some remaining open issues. These involve the best choice of upfront chemotherapy, the duration and intensity of frontline treatment, the value of consolidation radiotherapy, the role of functional imaging in treatment planning and monitoring and the adequacy of risk stratification tools. These observations have led us to investigate whether intensification of front-line ABVD would be possible while maintaining acceptable levels of toxicity and improving the performance of the schedule. We designed a dose-dense three-weekly version of the ABVD regimen (six cycles), which was also dose intensified, in the first four cycles, by escalating doxorubicin dose from 50 to 70 mg/m2 per cycle, in the absence of consolidation RT. A series of 172 patients (advanced-stage=124, intermediate-stage=48) was studied. Apart from pre- and post-Tx staging, all patients also underwent 18F-FDG-PET imaging after the 2nd cycle (PET2); in case of pathologic uptake at PET2, a new scan was performed after the 4th cycle (PET4). Open-label phase study began I June 2004; specifications are contained in the published article (Russo F BHJ 166,1118,2014) focused on feasibility and toxicity in 82 patients. The demographics and clinical characteristics are in Tab1.Ninety-five percent of patients completed the planned six cycles (median duration time=16.7 weeks). Median actual dose intensities were 20.94 (23.12 cycles1-4), 6.69, 3.96 and 245 mg/m2/week for doxorubicin, bleomycin, vinblastine and dacarbazine, respectively. This corresponded to a 66.9% (85.0%, cycles 1-4) increase in dose intensity for doxorubicin, (total dose 380 mg/m2) and of 32% for the other agents, over standard ABVD. Intensified ABVD was highly tolerated with low rates of hospitalization during treatment, a low incidence of G3/ G4 events, low post-treatment cardiac and pulmonary toxicities and a very low rate of gonadic toxicity. Only two cases of second cancer have been recorded. PET2 was negative in 87% of patients (85% ADV,92%INT). Remarkably a CR rate of 94% (93% ADV, 98% INT) was achieved and EFS and OS at 7-years were 85% (79%ADV, 91% INT) and 96% (93%ADV, 98%INT) respectively (Tab2, Fig1). At univariate analysis (factors: Age, sex, LDH, IPS,B-symptoms, mediastinal bulky disease (MBD), E-disease, PET2, stage IV) the predictive factors of low CR rate were IPS≥3 (CR 89% vs 97%, p=0.03), and PET2pos (CR 65% vs 99%p<0.001). At multivariate analysis PET2 positivity (p<0.001) was the only independent risk factor predictive of low CR rate. Kaplan-Meyer 7yr-EFS was 77 and 78% (Log Rank 1.1, p=0.28) in MBD and no-MBD subsets, respectively. 7yr-EFS was significantly better in patients with PET2neg (87% vs 52% , log rank 24.7, p<0.001) and in patients with IPS 0-2 (88% vs 71% log rank 4.9, p=0.02). At Cox regression analysis PET2 was the only independent factor predictive of Event Free Survival.Intensified ABVD without radiotherapy seems to be adequately powered to exploit early disease chemo-sensitivity yielding high percentage of early negative PET2, high rate of response and survival, without new severe or critical short and long-term toxicities. Table 1TAB 1Advanced-stage(n=124)Intermediate-stage (n=48)CharacteristicsNo.%No.%Age, yearsmedian3229range15-7715 - 62>45 years2319510Gender, male64521837Ann Arbor stageII322648100III4032IV5242B symptoms88711531Mediastinal bulk5645919Extramediastinal bulk ≥10cm6524≥ 3 nodal areas involved99803675Spleen involvement2319Extranodal (stage II-III)8624Extranodal (stage IV )5141ESR (>50 mm/h)60481531IPS ≥ 3614948LDH ratio>151411225Histologic subtypeNodular sclerosis102824083Lymphocyte rich108510Mixed celluarity6536NOS6500Table 2Advanced stageIntermediate stageTab 2N%95%C.I.N%95%C.I.Final treatment response12310048100CR1159388 - 97479894–100NearCR/PR64.912.1Progression21.600Cycle 2 PET12410048100negative106854492positive181548Cycle 4 PET181004100negative1161375positive739125Events222148<CR6512progression2200early relapse 3-128624late relapse>12 months32122nd tumor22001st line treatment-related death11001-yr EFS8583-949594–1002-yr EFS8376-909183-994-yr EFS8274-897-yr EFS7970-889183-997-yr OS9386-1009793–100 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic and biologic significance of DNMT3B expression in older patients with cytogenetically normal primary acute myeloid leukemia.

DNMT3B encodes a DNA methyltransferase implicated in aberrant epigenetic changes contributing to leukemogenesis. We tested whether DNMT3B expression, measured by NanoString nCounter assay, associates with outcome, gene- and microRNA-expression and DNA methylation profiles in 210 older (≥60 years) adults with primary, cytogenetically normal AML (CN-AML). Patients were dichotomized into high versus low expressers using median cut. Outcomes were assessed in the context of known CN-AML prognosticators. Gene- and microRNA-expression, and DNA methylation profiles were analyzed using microarrays and MethylCap-sequencing, respectively. High DNMT3B expressers had fewer complete remissions (CR; P=0.002) and shorter disease-free (DFS; P=0.02) and overall (OS; P<0.001) survival. In multivariable analyses, high DNMT3B expression remained an independent predictor of lower CR rates (P=0.04) and shorter DFS (P=0.04) and OS (P=0.001). High DNMT3B expression associated with a gene-expression profile comprising 363 genes involved in differentiation, proliferation and survival pathways, but with only 4 differentially expressed microRNAs (miR-133b, miR-148a, miR-122, miR-409-3p) and no differential DNA methylation regions. We conclude that high DNMT3B expression independently associates with adverse outcome in older CN-AML patients. Gene-expression analyses suggest that DNMT3B is involved in the modulation of several genes, although the regulatory mechanisms remain to be investigated to devise therapeutic approaches specific for these patients.

Prognostic value of miR-96 in patients with acute myeloid leukemia

ObjectiveAberrant expression of miRNA (miR)-96 is associated with tumorigenesis and tumor progression in several solid cancers. However, little is known about the expression and prognostic value of miR-96 in acute myeloid leukemia (AML). Therefore, the aim of this study was to investigate the correlation of miR-96 expression with clinicopathological features and prognosis of AML.MethodsReal-time quantitative RT-PCR assay was performed to evaluate the expression levels of miR-96 in mononuclear cells from bone marrow or peripheral blood specimens in 86 patients with newly diagnosed AML.ResultsCompared with normal controls, miR-96 expression was significantly downregulated in patients with newly diagnosed AML (P < 0.001). In analysis of 14 diagnosis/CR-paired samples, the expression level of miR-96 was found markedly elevated in patients after treatment than before (P < 0.001). Moreover, lower levels of miR-96 were associated with a higher white blood cell count, bone marrow blast count (P < 0.001 and 0.022, respectively), and lower hemoglobin and platelet count (P = 0.036 and 0.033, respectively). Although the low-expression group seemed to have a lower CR rate (53.85% vs 70.0%), there was no significant difference between the two groups (P = 0.213). The low-expression group had a lower relapse-free survival (RFS) (P = 0.038) and overall survival (OS) (P = 0.022) compared with the high-expression group during a median follow-up of 20 months.ConclusionOur data demonstrated that the expression of miR-96 was downregulated in newly diagnosed AML patients and associated with leukemic burden, as well as RFS and OS. This suggests that miR-96 detection might become a potential biomarker of prognosis and monitoring in AML.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1434808553949498

Predictors Of Treatment Outcome With The Combination Of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone (CRd) In Newly Diagnosed Multiple Myeloma (NDMM)

Predictors Of Treatment Outcome With The Combination Of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone (CRd) In Newly Diagnosed Multiple Myeloma (NDMM)

Frontline Intensive Chemotherapy Brings Survival Benefit In Young, Risky Patients With Follicular Lymphoma: Pair-Matched Analysis From The Czech Lymphoma Study Group (CLSG) Database

BackgroundFollicular lymphoma (FL) is a disease with very heterogeneous course ranging from the indolent forms to rapidly progressive cases with poor outcome. Optimal therapy in FL patients with high tumor burden is immunochemotherapy (R-CHOP is the most frequent regimen used), followed by maintenance treatment. Data from randomized prospective studies (PRIMA) showed poorer outcome in those with high risk disease in terms of lower CR rate, higher risk of relapse and lower efficacy of maintenance therapy. Data comparing up-front intensive approach in younger fit patients and R-CHOP are limited. AimTo analyze long term results of intensive treatment protocol (R-sequential chemotherapy) in comparison with age, FLIPI and maintenance delivery matched (R-CHOP) controls. MethodsHere we analyzed data of 48 prospectively enrolled FL patients who were treated by sequential (R-SQ) chemotherapy with or without up-front autologous stem cell transplant (ASCT) as a part of stratified risk adapted treatment in one institution. For R-SQ regimen were indicated patients<65 years with INT-FLIPI (with at least 2 additional risk factors: bulk and/or elevated B2M>3mg/L and/or thymidine kinase>15 IU/L) or HIGH-FLIPI patients (irrespective of additional risk factors). R-SQ protocol consists of alternating three cycles of etoposide-doxorubicine regimen (PACEBO), one methotrexate-ifosfamide regimen (IVAM), and one cycle of high dose cytarabine regimen (HAM). Remission was consolidated with 6th cycle of chemotherapy (PACEBO) in INT-FLIPI patients (n=22, 46%) or with ASCT with BEAM-200 conditioning (n=26, 54%) in HIGH-FLIPI patients. Maintenance immunotherapy was applied for historical reasons in 24 patients (50%). Controls were randomly selected from the Czech Lymphoma Study Group (CLSG) database from 626 cases with confirmed FL grade I to IIIa, treated with R-CHOP. Pair matching was performed on 1:3 basis, controls were matched by age, FLIPI and rituximab maintenance application. In the end, we analyzed intensive SQ-group (n=44) and standard control R-CHOP-group (n=144). Maintenance therapy was delivered to 24 patients (50%) in R-SQ group and to 72 patients (50%) in R-CHOP-group (P=1.00). ResultsMedian age of SQ-group was 47.6 years compared to 48.7 years in R-CHOP (P=0.44), FLIPI index was equally distributed: INT-FLIPI (43% vs 43%), HIGH-FLIPI (57% vs 57%, P=1.00). Treatment response quality was higher in SQ-group than in R-CHOP-group: CR/CRu 93.8% vs 70%, PR 6.2% vs 23% and SD/PD 0% vs 8% respectively (P=0.01). During the follow-up, (median 3.5 and 6.1 years in R-CHOP and SQ-group respectively, P<0.01) 10 patients (20.8%) relapsed or progressed in the R-SQ-group, and 41 (29%) in the R-CHOP-group (P=0.01). Only two of 48 patients (4.2%) died in the R-SQ-group, whereas twelve (8.7%) died in the R-CHOP-group (P=0.03). Five-year progression-free survival (PFS) was superior in the R-SQ-group with 78.5% (95% CI 0.66-0.91) survival compared to 53.8% (95% CI 0.43-0.65, P=0.005, HR=0.37) in the R-CHOP-group. Five-year overall survival (OS) was 100% in the R-SQ-group and 91.9% (95% CI 0.86-0.97, P=0.027, HR=0.18) in the R-CHOP group. When analyzing patients who received maintenance therapy, we found no difference in OS (P=0.13), but there was still significant difference in 5-year PFS in favor of the R-SQ-arm (88.4% and 58.2%, P=0.034). ConclusionsIn risky FL patients, intensive front-line therapy brings about 24% advantage in CR rate, about 25% higher 5-year PFS (reduces risk of relapse/progression by 62%) and about 10% advantage in 5-year OS (reduces risk of death by 82%). Maintenance immunotherapy application overshadows OS but not PFS advantage of intensive chemotherapy. Finally, in younger physically fit risky patients, more intensive induction regimen leads to superior disease control a remission duration compared to standard R-CHOP. AcknowledgmentSupported by grants: LF-2013-004, IGA NT12193-5/2011 and PRVOUK-27/LF1/1. We would like to thank to all referring physicians: Jan Pirnos (Ceske Budejovice), Katerina Kubackova (FN Motol), Lucie Barsova (Liberec), Petr Kessler (Pelhrimov), Jitka Jakesova (Pribram), Milan Lysy (Usti n. Labem), Jindra Ciberova (Znojmo), Dagmar Adamova (Opava), Milan Matuska (Ostrava), Martin Brejcha (Novy Jicin). [Display omitted] Disclosures:Trneny:Roche: Honoraria, Research Funding.

Lenalidomide (LEN) Combined To Intensive Chemotherapy (IC) In AML and Higher Risk MDS With Del 5q. Results Of a Phase I/II Study Of The Groupe Francophone Des Myelodysplasies (GFM)

BackgroundContrary to the “5q syndrome”, prognosis of higher risk MDS with del 5q, ie with increased marrow blast % and/or additional cytogenetic abnormalities (abn) and of AML with del 5q (isolated or complex) is poor. Those patients (pts) respond poorly to IC with 20-30% CR, of short duration (Estey, Hematologica 2000) and to azacytidine (Itzykson, Blood 2011). In a phase II study of LEN in higher risk MDS or AML with del 5q, 28% patients responded, but responses were restricted to isolated del 5q (Ades, Blood 2008). This prompted us to combine IC and LEN in higher risk MDS and AML with del 5q. MethodsThis phase I/II escalating dose study (NCT00885508) combined induction daunorubicin (DNR 45 mg/m2/d d1-3 in cohort 1, escalated to 60 mg/m2/d d1-3 in cohorts 2 and 3 ) + AraC (200mg/m2/d d1-7) to LEN (10 mg/d d1-21 in cohorts 1 and 2, escalated to 25 mg/d d1-21 in cohort 3). Pts with IPSS int 2 or high MDS or AML with del 5q (isolated or not) were eligible. Responders, ie with CR, CRi or marrow CR according to AML or MDS response criteria received 6 consolidation courses of AraC (120 mg/m2/d d1-5) + DNR (45 or 60 mg/m2 d1), and LEN (10 or 25 mg/d d1-15), with similar daily doses of DNR and LEN as for induction, followed by maintenance LEN (10 or 25mg/d) until progression. ResultsBetween Feb 2009 and May 2012, 82 pts were included, 31, 32 and 19 in cohorts 1,2 and 3 respectively. M/F was 42/40, median age was 66 years (IQR: 58-72). 1 patient had RAEB-1, 20 RAEB-2, and 61 had AML (including 21 FAB-RAEB-T, with 20%-30% marrow blasts). 79% pts had complex Karyotype (median number of 7 abn, range 3-17), 10% had isolated del 5q and 11% had del 5q+1 abn. Median baseline WBC was 2.6 G/l (IQR: 1.7-4.2).5 pts had early death related to severe sepsis in 3, multiorgan failure in 1 and myocardial infarction in 1 pt. 38 of the 82 patients (46%) achieved CR, 4 CRi, 8 PR, 32 had induction failure or progression, leading to an overall response rate (ORR) of 61% (95%CI:49.6-71.6%). The response rate (61%, 62% and 58% respectively) and CR rate (45%, 50 % and 42%) did not significantly differ in cohorts 1,2 and 3. Overall, 59% of the pts achieved cytogenetic response (CyR), 44% complete and 15% partial. 56%, 50% and 75% CyR were seen in patients with complex karyotype, del5q+ 1 abnormality and isolated del 5d respectively. 44%, 25% and 75% of the pts with complex karyotype, del5q+ 1 abnormality and isolated del 5d achieved CR. Two factors significantly predicted lower CR rate: WHO diagnosis (AML 40% vs MDS 66%, p=0.034) and higher marrow blast % (p=0.042).Overall, 117 consolidations courses were administered and 15 patients received allogeneic SCT. 36 (72%) of the 50 responders subsequently relapsed, with a cumulative incidence of relapse at 1 year of 82.8% (95%CI: 69.7-96.0). In responders, median DFS was 5.8 months (95%CI: 4.6-7.5). Forty-four patients had died, 15 of them within 90 days of treatment onset (early death) leading to an early death rate of 18.9% (95%CI: 14.7-31%). Median overall survival was 7.1 months (95%CI: 6.5-9.4), and 1 year OS estimated at 26.6% (95%CI: 15.6-45.4). Prognostic factors of shorter OS were higher WBC count (p= 0.01), higher marrow blast % (p= 0.005) and poorer performance status (p=0.046) while cytogenetic complexity and treatment cohort had no influence. In a multivariate Cox model, only higher marrow blasts remained of prognostic value. No difference in outcome was observed between treatment cohorts.Median duration of hospitalization during induction treatment was 30 days (IQR: 26-35) without difference across the 3 cohorts. Grade III-IV non-hematological toxicities included transient liver toxicity with an increase in transaminases (n=11), increase in creatinine level (n=2), Lung disease (n=11) related mainly to sepsis. Of note, grade III-IV increase in transaminases was mainly observed in the 25 mg Lenalidomide cohort (n=6/19, 31%) compared to 5/63 (8%) in pts who received 10 mg, suggesting that the dose limiting toxicity was reached at this dose level. ConclusionIntensive anthracycline AraC chemotherapy and LEN can be combined in higher risk MDS and AML with del 5q without unexpected additive myelosuppression. In this cohort of elderly pts with very poor risk cytogenetics (most had very complex karyotype), the ORR rate was 61% and CR rate 46% (with cytogenetic response in most responders), a higher response rate than generally reported with IC alone in similar pts. DFS remained however short, requiring further improvements Disclosures:Off Label Use: LEN in AML. Fenaux:CELGENE: Research Funding.

Expression of survivin in patients with acute myeloid leukemia

Objective of this study was to detect the expression of Survivin in acute myeloid leukemia (AML) and investigate the relationship of its expression levels with clinical variates and its correlations with BCL-2 ,Bcl-xL and MCL-1. The expression of Survivin, BCL-2, Bcl-xL and MCL-1 were measured by immunohistochemistry in bone marrow biopsy of 63 newly diagnosed AML patients, and the relationship between its expression level and clinical parameters (age, sex, WBC count, diagnosis, prognosis), especially fusion protein AML1/ETO was investigated. The results showed that the expression level of Survivin in newly diagnosed AML patients was higher than that of normal controls (P < 0.01), the expression levels of Survivin did not correlate with age, sex, and WBC counts of patients and so on. There was no significant difference of Survivin expression between different NCCN prognosis groups, either between patients with AML1/ETO or FLT3-ITD mutation and the other patients. Survivin positive patients were got to have lower CR rate but higher relapse rate, however that was not significant in statistics. Indeed, the cumulative survivin rate of Survivin positive patients were lower than that of Survivin negative patients (P = 0.04). Finally, positive correlation between Survivin and MCL-1 was also observed (r = 0.639, P = 0.000). It is concluded that overexpression of Survivin are closely related with occurrence and development of acute leukemia, and may be used as an indicator of prognosis evaluation. In addition, Survivin and MCL-1 may have a relationship of cooperation or interaction.

Time Elapsed from AML Diagnosis to Induction Chemotherapy Affects Overall Survival

We aimed to study the effect of elapsed time from AML diagnosis to treatment (TDT) on OS in a group of patients from public Hospital in Brazil. 41 AML (23 M, 18 F, 41 yrs, 18 - 84 yrs, from 2001 to 2004). There were 38 de novo AML and 3 secondary, median TDT was 6 days (range 1 - 82 d); the young ones were treated earlier than old ones (TDT 4 days vs 11, p = 0.07). Longer TDT (>10 d) was associated with worse CR rates (p = 0.02) and OS (p = 0.04). When patients were categorized into TDT from 1 - 4 d (I) vs >5 (II), those from I presented better OS than II (p = 0.004). When TDT was longer than 7 days OS decreased even more. Hb was higher in patients with TDT I vs II (8.3 vs 7.5 g/dL, p = 0.03) but WBC (p = 0.34) and platelet count (p = 0.75) were not different. Patients with TDT of 10 d were younger than TDT > 10 d (median age 41 vs 70 yrs, p = 0.001). The OS was 15.1% in 2 yrs and 8.6% in 7 yrs. Our data suggest longer TDT, when analyzed continuously, predicted for lower CR rates and OS rates.

The Clinical Role of Micrornas (miRs) in Cytogenetically Normal (CN) Acute Myeloid Leukemia (AML): miR-155 Upregulation Independently Identifies High-Risk Patients (Pts)

Abstract 1387▪▪This icon denotes a clinically relevant abstractmiR-155 is upregulated in aggressive subtypes of solid tumors and leukemia. In AML, higher miR-155 expression is associated with FLT3-ITD. However, whether miR-155 upregulation impacts on clinical outcome independently from FLT3-ITD and other prognosticators is unknown. We evaluated the prognostic impact of miR-155 in 363 CN-AML pts (153 age <60 y; 210 age ≥60 y) that were treated with cytarabine-daunorubicin-based regimens and had a median follow-up of 7.9 y (range, 2.3–12.9). miR-155 levels were measured in pretreatment marrow or blood by the NanoString nCounter assay quantifying expression of the encoding gene MIR155HG; other molecular markers were assessed centrally. High miR-155 expressers (miR-155) had higher WBC (P<.001) and were more often FLT3-ITD-positive (pos; P<.001), RUNX1-mutated (mut; <.001), WT1-mut (P=.03), ↑ ERG (P=.02) and ↑ BAALC (P=.002), and less often CEBPA-mut (P=.003), IDH2-mut (P=.004) and FLT3-TKD-pos (P=.08) than low expressers (↓ miR-155). ↑ miR-155 had lower CR rates (P<.001), shorter DFS (P=.001) and OS (P<.001), than ↓ miR-155. In multivariable analyses (MVA; Table), ↑ miR-155 was associated with lower CR rates (P=.007) and shorter OS (P<.001). Among younger pts, ↑ miR-155 had lower CR rates (P=.03) and shorter DFS (P<.001) and OS (P<.001) than ↓ miR-155. In MVA (Table), ↑ miR-155 status remained associated with worse CR rate (P=.06), shorter DFS (P=.003) and OS (P=.01). Among older pts, ↑ miR-155 had lower CR rates (P=.008) and shorter OS (P<.001); in MVA (Table), ↑ miR-155 remained associated with worse CR (P=.03) and shorter OS (P=.05). In the European LeukemiaNet classification, younger ↑ miR-155 in the Favorable (Fav) Genetic Group (GG; CEBPA-mut and/or NPM1-mut without FLT3-ITD) had lower CR rates (P=.03) and shorter DFS (P=.04) and OS (P=.02) than ↓ miR-155. In the younger Intermediate-I (Int-I) GG pts (with wild-type CEBPA, NPM1-mut with FLT3-ITD, or wild-type NPM1), miR-155 expression did not impact independently on outcome. In older pts, ↑ miR-155 had a shorter OS both in the Fav (P=.06) and Int-I GGs (P=.05) than ↓ miR-155. To gain biologic insights, we derived an Affymetrix gene-expression signature that comprised 196 mRNAs significantly correlated with miR-155 expression. Consistent with previous mechanistic studies, Gene Ontology analysis revealed that the ↑ miR-155-associated signature was enriched for genes involved in anti-apoptotic, proliferative and inflammatory activities (FDR<0.05). ↑ miR-155 was not significantly correlated with that of any other microRNAs (miRs) thereby supporting the unique role of miR-155 among the miRs in AML. In summary, miR-155 expression is independently associated with clinical outcome in CN-AML and may allow for better evaluation of molecular risk, especially in pts lacking FLT3-ITD, like those in the ELN Fav GG. Moreover, given its role in deregulation of fundamental mechanisms of cell homeostasis and the emergence of miR inhibitors, miR-155 may become a novel therapeutic target.TableMVA in pts with primary CN-AMLGroupCRDFSOSORPHRPHRPAll ptsmiR-155 expression not significantly associated with DFSamiR-155, ↑ v ↓0.46.0071.62<.001NPM1, mut v wt2.42.005BAALC, ↑ v ↓0.37.0022.16<.001WBC, each 50 units0.65<.001Age group, older v younger0.43.0032.38<.001FLT3-ITD, pos v neg1.78<.001Race, white v nonwhite1.62.03Pts age < 60 ymiR-155, ↑ v ↓0.39.062.13.0031.84.01RUNX1, mut v wt0.21.01Age, each 10 y increase0.45.004WBC, each 50 units1.49<.001FLT3-ITD, pos v neg2.82<.0011.82.01FLT3-TKD, pos v neg3.27<.001BAALC, ↑ v ↓2.66<.0012.33<.001Race, white v nonwhite2.81.02CEBPA, mut v wt0.47.02WT1, mut v wt2.25.005Pts age ≥ 60 ymiR-155 expression not significantly associated with DFSmiR-155, ↑ v ↓0.46.031.36.05NPM1, mut v wt2.45.03BAALC, ↑ v ↓0.32.0042.18<.001WBC, each 50 units0.65.005Age, each 10 y increase0.48.02FLT3-ITD, pos v neg1.56.006↑, high expression; ↓, low expression; CR, complete remission; DFS, disease-free survival; HR, hazard ratio; mut, mutated; neg, negative; OR, odds ratio; OS, overall survival; pos, positive; WBC, white blood count; wt, wild-type.Odds ratios > (<) 1.0 mean higher (lower) CR rate and HRs > (<) 1.0 mean higher (lower) risk of relapse or death (DFS) or death (OS) for the higher values of continuous variables and the 1st category listed for categorical variables. Disclosures:No relevant conflicts of interest to declare.

Monosomal karyotype in acute myeloid leukemia predicts adverse treatment outcome and associates with high functional multidrug resistance activity

Monosomal karyotype (MK) reflects highly unfavorable prognosis in patients with acute myeloid leukemia (AML). This study aimed to study the association of AML-MK with multidrug resistance (MDR) functional activity. A total of 369 AML patients (excluding APL) between 1995 and 2008 at a single center were included retrospectively. Functional MDR activity was evaluated with rhodamine-123 efflux activity with/without verapamil inhibition. MK was noted in 23 patients, only among whom classified into unfavorable cytogenetic risk group. Unfavorable cytogenetic subgroup with MK showed shorter OS (8.7 ± 5.9% vs. 23.5 ± 7.5% at 3 years, P = 0.030), EFS (8.7 ± 5.9% vs. 19.0 ± 6.9% at 3 years, P = 0.029), and a lower CR rate (34.8% vs. 65.7%, P = 0.031) compared with unfavorable subgroup without MK. Functional MDR activity was significantly higher in the unfavorable cytogenetic group with MK compared to all other cytogenetic risk groups taken as a whole (P = 0.026) and showed a trend toward statistical significance when compared with the unfavorable cytogenetic risk group without MK (P = 0.06). AML patients harboring MK showed a poor outcome in terms of lower CR rate and worse EFS/OS, and the presence of MK appeared to be associated with higher MDR functional activity of leukemic blasts.

Poor Outcome of RUNX1-Mutated (RUNX1-mut) Patients (Pts) with Primary, Cytogenetically Normal Acute Myeloid Leukemia (CN-AML) and Associated Gene- and MicroRNA (miR) Expression Signatures,

Abstract 3454RUNX1 encodes the α subunit of core binding factor, a heterodimeric transcription factor required for normal hematopoiesis. Acquired RUNX1 mutations (muts) have been associated with poor clinical outcome in AML; however, prior studies analyzed pts heterogeneous for cytogenetics, age, AML type (primary or secondary), and treatment received [including allogeneic stem cell transplant (alloSCT) in 1st complete remission (CR1)] and contained limited data regarding the potential molecular drivers of the worse outcome. We report a relatively large study testing the prognostic impact of RUNX1 muts in primary CN-AML pts (n=392) treated similarly with intensive cytarabine/anthracycline-based 1st-line therapy and without alloSCT in CR1. This cohort comprised both younger [<60 years (y); n=173] and older (≥60 y; n=219) pts. Pretreatment marrow (n=303) and blood (n=89) were analyzed centrally for RUNX1 muts by PCR and direct sequencing, and for FLT3-ITD, FLT3-TKD, MLL-PTD and NPM1, CEBPA, WT1, IDH1, IDH2 and TET2 muts. Gene and miR expression profiles were derived using microarrays. RUNX1 muts were found in 12.5% of pts (8% younger, 16% older), and were associated with lower hemoglobin (P=.01), white blood cells (WBC; P=.04), and blood blasts (P=.006). RUNX1-mut pts harbored NPM1 (P<.001) and CEBPA muts (P=.06) less frequently than RUNX1-wild-type (RUNX1-wt) pts. RUNX1-mut pts had lower CR rates (P=.005 in younger; P=.006 in older), and shorter disease-free (DFS; P=.058 in younger; P<.001 in older), overall (OS; P=.003 in younger; P<.001 in older) and event-free (EFS; P<.001 for younger and older; Figures 1 and 2) survival than RUNX1-wt pts. In multivariable models, RUNX1 muts remained associated with lower CR rate (P<.001) and shorter DFS (P<.001), OS (P<.001), and EFS (P<.001; Table) after adjustment for clinical and molecular variables. [Display omitted] [Display omitted] Table 1Multivariable analysis for EFS according to RUNX1-mut status in all CN-AML ptsHREFSPRUNX1, mut v wt2.271.65–3.12<.001FLT3-ITD, ITD v no ITD1.571.27–1.95<.001WT1, mut v wt1.441.02–2.01.04WBC, continuous 50 unit increase1.131.04–1.23.006Age group, ≥60y v <60y1.801.46–2.22<.001Note: A hazard ratio (HR) >1 corresponds to a higher risk for higher values of continuous variables and the 1st level listed of a dichotomous variable.To gain biological insight, RUNX1 mut-associated gene and miR expression signatures were derived in CN-AML for the first time. Older, NPM1-wt pts were analyzed since RUNX1 muts are more common in this age group and are nearly exclusive from NPM1 muts, which have their own characteristic gene-expression signature. This yielded 484 probe sets representing 278 named genes differentially expressed between RUNX1-mut (n=31) and RUNX1-wt (n=45) pts (P<.001). Genes normally expressed in hematopoietic stem (HSC) and early progenitor cells, including DNTT, BAALC, MN-1, CD109, P2RY14, FOXO1 and FLT-3 were upregulated in RUNX1-mut pts, as were components of the Wnt-signaling pathway, LRP6 and TCF4, that promote self-renewal and proliferation of HSCs. Genes upregulated (SETBP1, RBPMS, and SLC37A3) and downregulated (CCNA1 and RNASE3) in AML stem cells relative to AML progenitors were similarly deregulated in the RUNX1-mut signature. B cell lineage genes BLNK, IGHM, IRF8 and several class II MHC molecules were upregulated in RUNX1-mut pts while CEBPA, a key promoter of granulopoiesis, was downregulated. Genes implicated in chemoresistance, GAS6, PRKCE, and PTK2, were upregulated and MYCN, a promoter of both proliferation and apoptosis of myeloid cells, was downregulated in RUNX1-mut pts. Seven miRs were differentially expressed between RUNX1-mut and RUNX1-wt pts. Two members of the let-7 tumor suppressor family, which represses self-renewal and promotes differentiation of stem cells, were downregulated, as was miR-223, a positive regulator of granulopoiesis. MiRs -99a and -100 were also downregulated and miRs -211 and -595 upregulated in association with RUNX1 muts.In summary, RUNX1 muts are twice as common in older CN-AML pts than younger. They negatively impact on outcome in both younger and older pts not receiving alloSCT in CR1. RUNX1-mut blasts have molecular features of normal/malignant stem cells and B cells, which may explain their chemoresistance and guide novel therapeutic approaches. Disclosures:No relevant conflicts of interest to declare.

Impact of Non High-Risk Chromosomal Abnormalities on the Outcome of Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma

Abstract 333Impact of Non High-Risk Chromosomal Abnormalities on the Outcome of Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Background:Despite novel therapeutic agents and high-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HCT), most patients eventually progress and die of their disease. Recent advances in cytogenetic, molecular and genomic studies have led to identification of several chromosomal and molecular abnormalities. These abnormalities are important predictors of response to therapy, progression-free survival (PFS) and overall survival (OS). On conventional cytogenetic (CC) analyses, del 13, t(4;14), t(14;16) and del 17p are considered high-risk (HR). On Fluorescence in situ hybridization (FISH) analysis, all except del 13 are considered HR (Munshi, N et al. Blood 2011 117: 4696–4700). However there are a number of chromosomal abnormalities whose significance is not clearly identified (non-HR). In this study we report the impact of these non-HR chromosomal abnormalities on the outcome of patients who received high-dose chemotherapy and auto-HCT. Methods:We performed a retrospective review of patients with multiple myeloma who underwent high dose chemotherapy followed by auto-HCT at the M.D. Anderson Cancer Center. Between 10/1991 and 12/2010, 1570 patients received auto-HCT. The results of CC studies were available for 1329 patients, either at diagnosis or at relapse, but before auto-HCT. The primary objective was to study the impact of non-HR chromosomal abnormalities on PFS and OS, and to compare them to patients without chromosomal abnormalities. Results:Patient characteristics and major outcomes are summarized in the attached Table. In 1329 patients with available CC analyses before auto-HCT, chromosomal abnormalities were identified in 405 (30%) patients. One-hundred and seven (7%) patients had known HR chromosomal abnormalities, while 298 (23%) patients had non-HR chromosomal abnormalities. Fifty (17%) patients with non-HR chromosomal abnormalities and 296 patients (32%) with normal CC achieved complete or stringent complete responses (CR + sCR) (p=0.0001). Median follow up in surviving patients was 36 months. Median PFS in patients with non-HR chromosomal abnormalities and normal CC were 18.2 months (95%CI: 16–22.7) and 32.7 months (95% CI: 27.8–36.3), respectively (p= <.0001) (Figure 1). The OS in patients with non-HR chromosomal abnormalities and with normal CC were 56.5 months (95% CI: 43.2–66.9) and 87.2 months (95%CI: 80.1–102.4), respectively (p= <.0001) (Figure 2). [Display omitted] [Display omitted] Conclusions:In this large single center study with a long follow up, we demonstrated that non-HR chromosomal abnormalities in myeloma are associated with a lower CR rate and shorter PFS and OS after auto-HCT. Further studies are needed to better define these non-HR abnormalities and their impact on prognosis.TABLE 1Normal (n= 924)Non-High Risk (n= 298)Median age at auto-HCT5759Age >65 at auto-HCT137/924 (14.8%)70/298 (23.4%)RaceWhite = 605 (65%) Black = 148 (16%) Other = 171 (19%)W = 202 (67%) B = 44 (14%) O = 52 (19%)GenderFemale = 391 (42%) Male = 533 (58%)F = 104 (34%) M = 194 (66%)Disease status at transplantFirst Remission = 799 (86%) Relapsed: 110 (12%) Unknown = 15 (2%)First Remission = 224 (75%) Relapsed = 72 (24%) Unknown = 2 (1%)Conditioning RegimenMelphalan or non melphalan = 198 (79%) Melphalan alone = 726 (21%)Melphalan or non melphalan = 57 (81%) Melphalan alone = 241 (19%)Final ResponsePD = 17 (1.8%) <PR = 132 (14%) PR = 278 (30%) VGPR = 194 (20%) CR = 221 (23%) sCR = 75 (8.1%) Unknown = 7PD = 20 (6.7%) <PR = 45 (15%) PR = 103 (34%) VGPR = 73 (24%) CR = 34 (11%) sCR = 16 (5%) Unknown = 7Progressed447/924 (48%)172/298 (57%)Died278/924 (30%)123/298 (41%)PD: Progressive Disease PR: Partial Remission CR: Complete ResponseVGPR: Very Good Partial Response sCR: Stringent Complete Response Disclosures:No relevant conflicts of interest to declare.

Time Elapsed From AML Diagnosis to Induction Chemotherapy Affects Overall Survival

Abstract 4262AML is a heterogeneous group of genetically diverse hematopoietic malignancies arising from blood cell progenitors and is considered an oncologic emergency. Patients present prognostic characteristics (specifically karyotype and age) that influence OS. Substantial progress achieved in AML therapy includes early chemotherapy initiation, aggressive large broad antibiotic usage, early antifungal prescription, RBC and platelet transfusions, HSCT, and development of new drugs. Most published AML data are from developed countries and only a few are from emergent ones in which the overall context is distinct. We aimed to study the effect of elapsed time from AML diagnosis to treatment (TDT) on OS in a group of patients from public Hospital Sao Paulo, Brazil. 41 consecutively AML patients were selected (23 males and 18 females, median age: 41 yrs, range 18 – 84 yrs) from Jan 1st, 2001 to Mar 31st, 2004 and last contact was on Jul 24th, 2011. AML diagnosis was set according to WHO classification and by G-banding karyotype (ISCN, 2009). Cytogenetic risk classification categories were adapted from MRC (Grimwade et al). Patients were treated with 3+7 daunorubicin (45mg/m2/d/3d), APL patients received ATRA-based regimen (Ruutu et al). Kaplan-Meier and student t-test were used. Results:38 were de novo AML and 3 secondary, median pretreatment WBC was 9.1/μ L (range 0.5–240/ μ L), median TDT was 6 days (range 1–82 d); 26 patients were young (<60yrs) and 15 old (>60 yrs). Cytogenetic risk distribution was: favorable 20.7%; intermediate 27.6%; unfavorable 27.6% and no metaphases 27.6%. 20 patients achieved CR (48.7%): 61.5% in the young group and 26.6% in the old. Median survival was 26.8 weeks (figure 1), 33 weeks for the young group and 10.7 weeks for the old (p =0.034). No statistical differences were found in Hb, WBC and platelet count among groups. Young patients tended to be treated earlier than old ones (TDT 4 days vs 11, p=0.07). An inverse correlation was seen in TDT with age, leukocyte, CR and OS. Longer TDT (> 10 d) was associated with worse CR rates (p=0.02) and OS (p=0.04). When patients were categorized into TDT from 1–4 d (I) vs > 5 (II), those from I presented better OS than II (p=0.004). When TDT was longer than 7 days OS decreased even more. Hb was higher in patients with TDT I vs II (8.3 vs 7.5 g/dL, p=0.03) but WBC (p=0.34) and platelet count (p=0.75) were not different. Patients with TDT of 10 d were younger than TDT >10 d (median age 41 vs 70 yrs, p=0.001). For the entire AML cohort OS was 15.1% in 2 yrs and 8.6% in 7 yrs. Discussion:The results showed that less than half of the patients reached CR. Younger patients presented better CR than elderly and this is similar to other series (Appelbaum et al; Juliusson et al). Despite chemotherapy regimen younger patients presented poorer OS compared to Northern Hemisphere series (Juliusson G et al). Several reasons account for such results: poorer PS, delayed diagnosis and bleeding and infectious complications. Elderly patients who were treated presented dismal OS and notably a median TDT almost three times longer than younger. Reasons for a longer TDT in AML were: significant comorbidities, severe infectious complications, and delay to start chemotherapy due to logistics reasons and the need to involve caregivers and family members to aid in decision making process. With more comorbidity in elderly population, reluctance toward intensive therapy is common and probable medical decision is critical with this.Therefore measures to shorten the TDT should be taken: address rapid AML diagnosis, evaluate and treat comorbidities, and develop a supportive and continuous system to promote early AML diagnosis and prompt treatment. Our data suggest longer TDT, when analyzed continuously, predicted for lower CR rates and OS rates therefore we need to address identify factors and start therapeutic measures to aid decision making and improve OS in AML patients in our country. Disclosures:No relevant conflicts of interest to declare.

Tailored temozolomide therapy according to MGMT methylation status for elderly patients with acute myeloid leukemia

Temozolomide sensitivity is determined by methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter. This study assessed whether the temozolomide dose can be tailored by MGMT promoter status and whether protracted, low-dose temozolomide can "prime" blasts in patients with unmethylated MGMT (unMGMT). Elderly patients with high-risk AML were stratified by MGMT methylation. Patients with methylated MGMT (mMGMT) received temozolomide 200 mg/m(2) orally for 7 days every 4 weeks, while patients with unMGMT received temozolomide 100 mg/m(2) orally for 14 days followed by 200 mg/m(2) orally for 7 days every 6weeks. Of 36 patients (median age, 75 years), 31 (86%) had an unMGMT promoter. Overall response rate for the entire cohort was 36%. Patients with mMGMT and unMGMT had similar response rates (40% vs. 29%). Median duration of response and overall survival (OS) among responders were 29 and 35 weeks, respectively. Induction deaths (ID) occurred in 25% of patients, mostly caused by disease progression. Hematological toxicities were the most common adverse event. Toxicities were similar between patients on conventional versus protracted schedules. High HCT-CI scores were predictive of lower CR rate, higher ID, and shorter OS, while bone marrow blast count <50% at screening predicted for improved responses. Temozolomide, dosed according to MGMT methylation status, demonstrated modest clinical activity in elderly patients with AML, especially in those presenting with fewer comorbidities and low disease burden. The trial was registered on www.ClinicalTrials.gov as #NCT00611247.

Retrospective analysis of prognostic factors associated with response and overall survival in patients with RAEB-t MDS treated with decitabine.

6598 Background: Response to decitabine, a hypomethylating agent for treatment of MDS of all FAB subtypes and Intermediate-1, Intermediate-2 and High-risk IPSS groups, was assessed using IWG 2000 criteria. The revised WHO definition of AML is ≥20% blasts instead of ≥30% blasts, so IWG updated its response criteria in 2006. The current analysis updates response data using IWG 2006 criteria. Methods: A retrospective analysis was conducted of a pooled subset of patients with MDS from two decitabine trials: 3-day dosing (phase III) or 5-day dosing (phase II). Patients with baseline marrow blasts ≥20% receiving decitabine (RAEB-t group) were compared with patients with baseline marrow blasts <20% (MDS group). Comparisons were made of baseline characteristics (Fisher’s exact test and t test); overall response rates (ORR) (Fisher’s exact test); and overall survival (OS) (log-rank test; significance p<.05). Results: The RAEB-t group (n=26) had a significantly shorter time from MDS diagnosis (7.3 vs 18.3mo), higher IPSS risk (76.9% vs 15.9% of patients), and lower median baseline platelet count (62.3 vs 112.7 x103/mL) vs the MDS group (n=157), yet the two groups still had similar OIR, PR, mCR, HI, stable disease, and disease progression. Adverse events were similar between groups. Conclusions: Based on this retrospective analysis, decitabine yielded a similar response rate in RAEB-t patients as in other MDS patients, except for a lower CR rate, consistent with the higher proportion of IPSS high-risk. Moreover, the RAEB-t patients did not progress to AML (≥30% blasts) more rapidly than the MDS population. As such, clinical responses in the RAEB-t group are encouraging. RAEB-t (n=26) n (%) MDS (n=157) n (%) P* ORR (CR+mCR+PR) 4 (15.4) 44 (28.0) 0.2311 OIR (CR+mCR+PR+HI) 9 (34.6) 67 (42.7) 0.5223 CR 0 25 (15.9) 0.0278 mCR 2 (7.7) 14 (8.9) 1.0000 PR 2 (7.7) 5 (3.2) 0.2602 HI 5 (19.2) 23 (14.7) 0.5589 Stable disease 8 (30.8) 43 (27.4) 0.8137 Progressive disease 4 (15.4) 27 (17.2) 1.0000 Abbreviations: CR, complete response; HI, hematologic improvement; mCR, marrow complete response; OIR, overall improvement rate; PR, partial response. *Fisher’s exact test.

Efficacy and Feasibility of Nelarabine Savage Therapy In Adult Relapsed or Refractory T Cell Acute Lymphoblastic Leukemia (T-ALL) and Lymphoblastic Lymphoma (T-LBL) Strongly Indicates the Introduction of a Nelarabine-Based First Line Regimen

AbstractAbstract 4335 Background.T-ALL represents 15% of childhood and 25% of adult ALL. Despite a cure rate of almost 80% in children and adolescents, adult ALL remains a difficult disease to cure, due to a high risk of relapse. Effective treatment of relapsed acute T-ALL is limited with a low CR rate, a high treatment-related mortality, and a very low prolonged disease-free survival.Nelarabine is a pro-drug of ara-G, approved by the FDA for the treatment of T-ALL and T-LBL that have not responded to or has relapsed after treatment with at least 2 chemotherapy regimens. Similar to other nucleoside analogues, Nelarabine acts by inhibiting DNA synthesis and inducing apoptosis in malignant cells. Aims of the study.To evaluate the safety profile and the efficacy of Nelarabine treatment as savage therapy, administered to 9 out of 13 adult relapsed or refractory T-ALL or T-LBL patients. Patients and Methods.After obtaining an informed consent, nine patients (median age 31 years, range 19–37, M/F= 9/0) affected by T-ALL (N=6) and T-LBL (N=3) received a savage therapy with Nelarabine (median cycle=1, range 1–3). Nelarabine was administered at standard adult dosage (1500 mg/sqm on days 1, 3 and 5, every 21). Seven patients were relapsed after two previous chemtotherapy regimens, including allogeneic bone marrow transplantation; the remaining two patients were primary resistant to standard induction treatment. Results.Five out of nine patients obtained a complete morphological remission (4 T-ALL patients and 1 T-LBL patient), whereas a partial remission was documented in two cases, with an overall response rate of 78%. Median duration of complete response was 6 weeks (range 3–6 weeks). Nelarabine was well tolerated, and no significant adverse events were registered. Extra- hematological neurological toxicity, not clearly related to the drug, occurred in two cases, determining, in one patient a complete and irreversible paraplegia, and in the second one a condition of mental confusion (grade III), which resolved after few days. Conclusion.In our experience Nelarabine was successfully administered in such a high risk patients population. The drug showed a relevant efficacy and a good safety profile, strongly suggesting a good rational for its introduction in first-line chemotherapeutic regimens. This strategy is being explored in our Institution as well as in other ones (Faderl S, MD Anderson). Acknowledgments.This work was supported by European LeukemiaNet, AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, Ateneo RFO grants, Project of integreted program (PIO), Programma di Ricerca Regione – Università 2007 – 2009. Disclosures:Baccarani:NOVARTIS: Honoraria; BRISTOL MYERS SQUIBB: Honoraria. Martinelli:Novartis: Consultancy, Honoraria; BMS: Honoraria; Pfizer: Consultancy.

A Phase III PETHEMA/GEM Study of Induction Therapy Prior Autologous Stem Cell Transplantation (ASCT) In Multiple Myeloma: Superiority of VTD (Bortezomib/Thalidomide/Dexamethasone) Over TD and VBMCP/VBAD Plus Bortezomib

AbstractAbstract 307 Introduction:In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing TD vs. VTD vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM followed by ASCT with MEL-200. Primary end points:response rate after induction and after ASCT and time to progression. Patients and Method:TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1–4 and 9–12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus bortezomib 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus bortezomib consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of bortezomib (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. From April 6, 2006 to August 5, 2009 the 390 planned patients entered the study. Four patients failed the eligibility criteria. 386 patients (median age: 56 yrs; M: 207, F: 179; IgG: 233, IgA: 85, light chain: 57, IgD: 9, Ig M: 2) were analyzed. The stage according to the ISS was I in 147 patients, II in 160, III in 75 and unknown in 4 and 66 patients (17%) had extramedullary soft-tissue plasmacytomas (EMP). Seventy out of the 330 patients (21%) with cytogenetic studies had high-risk cytogenetics (t(4;14), t(14;16), and/or 17p deletion). One-hundred and thirty patients were allocated to VTD, 127 to TD and 129 to VBMCP/VBAD/B. Prognostic factors, including cytogenetics, were similar in the 3 arms. Response, survival and toxicity were evaluated on an intention-to-treat basis. Responses reported by investigators were centrally reassessed. Result:The IFE negative CR rate was significantly higher with VTD (35%) compared to TD (14%) and VBMCP/VBAD/B (22%) (p=0.0001 and p=0.01, respectively). The progressive disease (PD) rate during induction was significantly lower with VTD than with TD (7% vs. 23%, p=0.001). In patiens with high-risk cytogenetics, the CR rate was significantly greater with VTD when compared with TD (35% vs. 0%, p=0.002) and with VBMCP/VBAD/B (35% vs. 22%, p=0.02). The CR rate to VTD in patients with 17p deletion was 58% while none of the patients with this cytogenetic abnormality responded to TD or to VBMVP/VBAD/B (p=0.03 and p=0.02, respectively). Of interest, the CR rate in patients with t(11;14) was significantly lower than in patients lacking this abnormality (11% vs. 27%, p=0.01). This low CR rate in patients with t(11;14) was similar in the 3 arms. In the overall series, PD was significantly higher in patients with EMP (24% vs. 11%, p=0.01) with a significantly higher PD rate for TD as compared to VTD (40% vs. 12%, p=0.02). The incidence of thrombotic events was 2%, 6% and 5% for VTD, TD and VBMCP/VBAD/B, respectively (p=NS). The frequency of grade ≥ 3 peripheral neuropathy was 12% with VTD compared to 1% in both the TD and the VBMCP/VBAD/B arms (p= 0.0002). Treatment was discontinued due to toxicity en 16 patients (VTD:9, TD:4, VBMCP/VBAD/B:3). Nine patients died during the induction period (3 in each arm). On an intention to treat basis, the post-ASCT CR rate was higher in the VTD arm compared with TD (46% vs. 24%, p=0.004) and VBMCP/VBAD/B (46% vs. 38%, p=0.1). The estimated overall survival (OS) at 4 years was 76% with no significant differences among the 3 arms. After a median follow-up of 27 months, the progression-free survival (PFS) was not reached with VTD while it was 27 and 38 months with TD and VBMCP/VBAD/B, respectively (p=0.006). In the overall series, patients with high-risk cytogenetics had a significantly shorter OS (p=0.00007) and PFS (p=0.004). In addition, when compared with the good-risk group, patients with high-risk cytogenetics showed a trend towards a shorter PFS either after induction with VTD (median not reached vs. 17 months, p=0.05) and with TD (median 28 vs. 15 months, p=0.09). Conclusion:Induction with VTD resulted in a significantly higher CR rate in both the overall series and in patients with high-risk cytogenetics. The post-ASCT CR rate was also significantly higher with VTD than with TD and there was a trend when compared with VBMCP/VBAD/B. Finally, VTD resulted in a significantly longer PFS. However, longer follow-up is required to establish whether or not VTD will overcome the poor prognosis of patients with high-risk cytogenetics. Disclosures:Rosiñol:Janssen-Cilag: Honoraria; Celgene: Honoraria. Off Label Use: Bortezomib and Thalidomide are not approve for first line in Spain. Cibeira:Janssen-Cilag: Honoraria; Celgene: Honoraria. Mateos:Janssen-Cilag: Honoraria; Celgene: Honoraria. Oriol:Janssen-Cilag: Honoraria; Celgene: Honoraria. García-Laraña:Janssen-Cilag: Honoraria; Celgene: Honoraria. De La Rubia:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sureda:Janssen-Cilag: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen-Cilag: Honoraria. Alegre:Janssen-Cilag: Honoraria; Celgene: Honoraria. Lahuerta:Janssen-Cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria, Speakers Bureau. Blade:Janssen-Cilag: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Analysis of CRLF2/JAK Expression and Mutation Status In Adult ALL Patients

AbstractAbstract 758Adult acute lymphoblastic leukemia (ALL) is a heterogeneous disease with low overall survival. Compared to pediatric ALL, outcomes for adults have not improved despite recent advances in therapy and treatment support. Novel targets and biomarkers will aid in the development of new therapeutic strategies. Recent studies described mutations in the cytokine receptor-like factor 2 (CRLF2), and Janus kinase 1 (JAK1) and JAK2 in ALL patients (pts). These activating mutations have been associated with poor outcome in adult and pediatric series. Interestingly, the gene expression profile (GEP) of pts with these abnormalities overlaps with Philadelphia chromosome (Ph) positive ALL GEP. In order to further assess the prognostic value of these genetic abnormalities in adult ALL we analyzed RNA from available pretreatment bone marrow (BM) and peripheral blood (PB) samples of 138 pts enrolled in SWOG studies S9400, and S0333.The expression levels of CRLF2 were examined in 85 available specimens with more than 50% blasts. B-glucoronidase, GUSB, was used to correct for RNA integrity. Expression fold change was calculated relative to the pool of RNA from the PB of 7 healthy donors using the comparative Ct analyses (2-DDCt). CRLF2 levels varied significantly in the examined population, ranging from no detectable expression to 8735-fold greater than the calibrator. High-expressers were defined by expression fold change 10-times above the median (n=21, 25%). Deletion of pseudoautosomal region 1 of chromosomes × and Y, with juxtaposition of the P2RY8 promoter to the CRLF2 coding region, was tested in 126 pts, and 20 pts were positive for P2RY8-CRLF2 (16%). Sixty-seven percent of CRLF2 high-expressers displayed this mutation (14 out of 21). CRLF2 point mutation F232C was identified in 6% of the samples (7 out of 126). Less than 2% of samples (1.6%, 2 out of 120) displayed JAK1 mutations (V658F and V658I). Seven percent of tested pts (9 out of 129) had JAK2 mutations: D869V, L884P, N622T, R683G, and R683S (1, 2, 1, 4, and 1 pts, respectively).CRLF2 over-expression, the presence of P2RY8-CRLF2, or mutations in CRLF2, JAK1, or JAK2 did not significantly correlate with, gender, age or baseline WBC. No significant correlation with outcome variables (CR, RD, RFS, or OS) was found when the cohort was analyzed as a whole, or when pts with known T-cell lineage ALL are excluded (n=115). Though not a statistically significant result, the two pts with JAK1 were reported living at 9 and 12 years of follow-up. Subgroup analysis of Ph negative non-T-ALL pts (n=86) showed a modest correlation of CRLF2 high expression with a lower CR rate (50% vs. 76% CR rate chi-square test p=0.046). However, this trend in CR rate is not seen in the analysis of continuous CRLF2 expression levels and overall survival is not significantly correlated with CRLF2 expression. Conclusion:Our results do not confirm previous reports of associations between clinical outcomes and expression of CRLF2 and mutations in CRLF2, JAK1 and JAK2 in adult and pediatric ALL. The discrepancy between previous and current studies may be attributed to differences in age (adult vs. children) or treatment protocol. CRLF2 is a potential therapeutic target and biomarker for response for pediatric and adult ALL. Disclosures:No relevant conflicts of interest to declare.

Combination Biologic Therapy as Initial Treatment for Follicular Lymphoma: Initial Results From CALGB 50701 - a Phase II Trial of Extended Induction Epratuzumab (anti-CD22) and Rituximab (anti-CD20)

AbstractAbstract 427Rituximab is effective as single agent therapy in the treatment of follicular lymphoma (FL), and when combined with chemotherapy has extended remissions and survival. Epratuzumab (Immunomedics), a humanized anti-CD22 monoclonal antibody, also has single agent activity in FL, and in combination with rituximab led to durable complete responses in the treatment of patients (pts) with relapsed and refractory indolent NHL. To evaluate the hypothesis that combining a second biological agent with rituximab might improve efficacy with good tolerability, the CALGB treated 60 previously untreated pts with epratuzumab and rituximab in a multicenter phase II trial and we report here the preliminary response and toxicity findings. Rituximab was administered at 375 mg/m2 iv weekly for four weeks, then every 8 weeks for four additional doses for a total of 8 doses over 9 months. Epratuzumab, was given at 360 mg/m2 two days before the first rituximab dose to assess toxicity. From week 2 on, epratuzumab was given before the rituximab on the same day for a total of 8 doses over 9 months. Fifty-seven evaluable pts were enrolled between May 2008 and September 2009. FLIPI scores at study entry were 13 (22%) low; 28 (47.5%) intermediate; and 18 (30.5%) high. Fifty-three pts completed all therapy through month 9. One pt was taken off therapy due to progression after month 5. One pt died during induction from line sepsis. Two pts were taken off study due to adverse events, 1 during induction (grade 4 thrombosis and MI), 1 following month 5 (dyspnea, hypoxia and pulmonary NOS). All other toxicities were grade 3 or lower, including fatigue (grade 3 3%, grade 2 17%), nodal pain (grade 3 5%, grade 2 8%), and cytokine release and pruritis (grade 2, 5% each). To date, there have been 19 CRs (33.3%), 29 PRs (50.9%)(ORR 84.2%); 9 (15.8%) had stable disease. All 19 CR patients completed all treatment. The mean time to CR was 9 months. Two patients progressed after a period of stable disease, and 25 of the 29 patients who achieved PR remain in response. All 19 CRs also remain in remission at this point with a median follow-up of 0.82 years (range 0.52 to 2.0). FLIPI score was not predictive of response. The CR rate in low risk pts was 31%, 44% in intermediate risk and 18% in high risk pts. There was a trend toward higher CR rate among patients with FcgR2A His (n=10, CR 60%) and to a lower CR rate among those with FcgR2A Arg (n=14, CR 14.3%). Correlations with PET scan at week 3, with tissue biomarkers and to statin use are being analyzed. Rituximab and epratuzumab is an effective and very well tolerated regimen with an ORR of 84% in previously untreated patients with follicular lymphoma. Disclosures: Off Label Use:Use of Epratuzumab, a humanized antiCD22 monoclonal antibody in treatment of follicular lymphoma. Leonard:BiogenIDEC: Consultancy; Genentech: Consultancy; Immunomedics: Consultancy. Jones:Glaxo Smith-Kline: Consultancy; Abbott: Research Funding. Cheson:Genentech: Consultancy.

Clinical Significance of Granulocytic Sarcoma at Relapse In Adult Patients with Acute Myeloid Leukemia

AbstractAbstract 4373 BackgroundWe reported that adult AML patients with granulocytic sarcoma (GS) at diagnosis were associated with younger age, higher WBC counts, and monocytic differentiation of leukemia cells and GS adversely affected relapse rate and DFS at the 51st ASH annual meeting. However clinical impact of GS at relapse has not been clear. The objective of this study was to describe the frequency and clinical characteristics of adult AML patients with GS at relapse. MethodsBetween January, 1990 and March 2010, 517 patients (median age 57 (15-88), male/female; 313/204) diagnosed as AML were included. 58 patients (11.2%) were with GS at diagnosis and 459 patients were without GS. 480 younger patients were treated according to Japan Adult Leukemia Study Group treatment protocols (JALSG AML92, AML95, AML97, GML200, or AML201). 37 older patients were treated with low-dose Ara-C based regimen. The χ2-test was used for the binary variable comparison. The Mann-Whitney U test was used for continuous variable comparison. P < 0.05 was considered to indicate statistical significance. ResultsA total of 295 relapses was occurred in 233 patients. 32 relapses (11.0%) were with GS and 263 were without GS. 30 patients with GS at relapse had the same characteristics as patients with GS at diagnosis, including younger age (p<0.001), higher WBC counts at relapse (p=0.045), and high frequency of FAB M4 (p=0.001) and M5 (p=0.042) morphology. No significant differences in sex, the distribution of cytogenetic risk groups, and the frequency of each cytogenetic change including t(8;21), 11q23, inv(16), and the complex karyotype demonstrated. 38 relapses occurred in 34 patients with GS at diagnosis and 257 relapses in 199 patients without GS. The frequency of relapse with GS in patients with GS at diagnosis was significantly higher than that in patients without GS (29% vs 8%; p=0.0006). 41 relapses occurred in 37 patients after allogenic stem cell transplantation (allo-SCT) and 254 relapses in 196 patients after chemotherapy. 8 patients received allo-SCT from peripheral blood stem cell, 24 from bone marrow, and 6 from cord blood. 31 patients received conditioning regimen containing total body irradiation (TBI) and 6 received non-TBI regimen. The frequency of relapses with GS after allo-SCT was significantly higher than that after chemotherapy (27% vs 9%; p=0.0035). In patients after allo-SCT cell source and conditioning regimen did not affected frequency of GS. 58% of patients achieved CR with any salvage chemotherapy. Patients with GS had a trend of a lower CR rate than without GS (47% vs 63%; p=0.068). ConclusionsPatients with GS at relapse had the same characteristics as patients with GS at diagnosis, including younger age, higher WBC counts, and monocytic differentiation of leukemia cells. This study shows the high frequency of relapse with GS in patients with GS at diagnosis and after allo-SCT independently of cell source and the conditioning regimen. As patients with GS at relapse tended to get chemotherapy-resistant we should give the attention to relapse with GS in follow-up of such AML patients. Disclosures:No relevant conflicts of interest to declare.